Pseudomonas aeruginosa is the single most frequently isolated Gram-negative aerobic bacterium from hospital intensive care units (ICUs) and the most frequent bacterium isolated from the respiratory tract of ICU patients. P. aeruginosa pneumonia and septicemia in immunocompromised patients have directly attributable death rates approaching 30%. P. aeruginosa is one of the most common and lethal pathogens, notably responsible for ventilator-associated pneumonia in intubated patients, with mortality approaching 40%. P. aeruginosa also plays a key role in the pathogenesis of cystic fibrosis, bronchiectasis, and chronic obstructive pulmonary disease, as well as extrapulmonary diseases such as urinary tract infections, skin infections in hospital burn units, and surgical wound and bloodstream infections. In view of its recognized clinical impact, the increasing frequency of multi-drug-resistant P. aeruginosa is concerning as second- and third-line antibiotics are severely limited by their increased cost and toxicity. Thus, there is an urgent need to develop alternative therapies for P. aeruginosa lung infections. In this R21 grant application, we propose to explore a unique and innovative approach to treat P. aeruginosa infections using a shed MUC1 ectodomain (MUC1-ED) decoy receptor to selectively inhibit adherence of the bacteria to host cells. The Specific Aims are: 1) To define the mechanisms through which NEU1-mediated MUC1-ED desialylation generates a decoy receptor that protects against P. aeruginosa infection, and 2) To develop the recombinant MUC1-ED protein backbone as a therapeutic agent against invasive P. aeruginosa infection. If this high-risk/high-reward project is successful, it will result in the identification of a novel class of anti-infective agents against P. aeruginosa. Our approach is fundamentally different from traditional antibiotic strategies that target the microorganism itself, and is expected to be highly complementary with direct antibacterial approaches. Finally, if this project is successful, a similar strategy might be applied to treat other flagellated bacteria infecting mucosal surfaces.